US10344021B2 - Process for the separation of enantiomers of piperazine derivatives - Google Patents

Process for the separation of enantiomers of piperazine derivatives Download PDF

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US10344021B2
US10344021B2 US16/078,715 US201716078715A US10344021B2 US 10344021 B2 US10344021 B2 US 10344021B2 US 201716078715 A US201716078715 A US 201716078715A US 10344021 B2 US10344021 B2 US 10344021B2
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ethyl
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US20190062316A1 (en
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Anna Quattropani
Santosh S. Kulkarni
Awadut Gajendra Giri
Johannes Nicolaas Koek
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Asceneuron SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to a process for preparing either enantiomer of piperazine derivatives, and to enantiomerically pure or enriched piperazine derivatives by chiral resolution in the presence of a non-racemic, chiral acid.
  • the invention relates particularly to a process for preparing either enantiomer of a compound of formula I:
  • X denotes O or CH 2 ,
  • Y is NH or N-PG
  • PG denotes a protective group
  • n denotes 0 or 1
  • Enantiomers of compounds of formula I are useful as drugs or building blocks for the synthesis of drugs, such as but not limited to glycosidase inhibitors.
  • PCT/EP2015/069598 describes e.g. N-(5- ⁇ 4-[(1S)-1-(2,3-dihydro-1-benzofuran-6-yl)ethyl]piperazin-1-yl ⁇ -1,3,4-thiadiazol-2-yl)acetamide and N-(2- ⁇ 4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl ⁇ pyrimidin-5-yl)acetamide as active glycosidase inhibitors having high inhibitory activities.
  • the present application provides processes for the preparation of either enantiomer of compounds of formula I above and in particular (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine, with high enantiomeric excess (e.e.), preferably with >95% e.e. or >98% e.e., comprising the selective crystallization of the respective racemic compound of formula I in the presence of a chiral acid yielding the crystallization of a strongly enantiomerically enriched salt form and leaving in solution the majority of the other enantiomer as a salt.
  • the free base of each of the respective entantiomers can be obtained by e.g. aqueous basic treatment and extraction from aqueous phase with suitable solvents, as further described below.
  • X denotes 0 or CH 2 .
  • Y is NH or N-PG
  • PG denotes a protective group
  • n denotes 0 or 1
  • X, Y and n are as defined above.
  • the compounds can be prepared from the corresponding ketone (II) by reductive amination with amine (V), using conditions known to the one skilled in the art, such as but not limited to the use of NaBH(OAc) 3 as reducing agent, in the presence of one equivalent of AcOH in DCE.
  • reductive amination can be performed in two steps, with first imine formation, that can be catalysed by Ti(OiPr) 4 , followed by reduction with suitable reducing agent, such as but not limited to NaBH 4 in MeOH (Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).
  • ketone (II) can be reduced into the corresponding alcohol (III) using usual reductive agents such as NaBH 4 in an alcoholic solvent, such as MeOH. Alcohol functionality can be then transformed into a suitable leaving group LG, such as but not limited to Cl or OMs, using conditions known to a person skilled in the art.
  • LG such as but not limited to Cl or OMs
  • the addition of amine (V) to intermediate (IV) would yield the formation of compound (I).
  • Compounds of formula I, wherein Y is NH can be obtained by removal of the group PG of compounds of formula I, wherein Y is N-PG, under standard conditions known to those skilled in the art.
  • a “leaving group” LG denotes a chemical moiety, which can be removed or replaced by another chemical group.
  • the term leaving group preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • LG When a leaving group LG is attached to an aromatic or heteroaromatic ring, LG can denote in addition SO 2 -alkyl or F. Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters are advantageously formed in situ, for example through addition of HOBt, N-hydroxysuccinimide or HATU.
  • PG denotes a protecting group, which is compatible with the chemistry described above, such as but not limited to BOC (tert-butoxy-carbonyl), or SO 2 Tol (toluolsulfonate). It can be removed under acidic conditions, such as but not limited to HCl in MeOH or dioxane or TFA in DCM for e.g. the BOO protecting group. Alternatively, a mixture of HBr, AcOH and 4-hydroxybenzoic acid or a mixture of H2SO4 and trifluoroacetic acid at temperatures ranging from RT to 100° C. can be used to cleave a sulfonamide protecting group, such as para-toluene sulfonamide. The removal of the protecting group PG yields the corresponding amine.
  • BOC tert-butoxy-carbonyl
  • SO 2 Tol toluolsulfonate
  • Preferred groups PG are the following: Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, 9-Fluorenylmethyloxycarbonyl (FMOC) group, Alkanoyl group, such as the Acetyl (Ac) group, Benzoyl (Bz) group, Benzyl (Bn) group, Carbamate group, p-Methoxybenzyl (PMB), 4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, Arylsulfonyl group such as the Tosyl (Ts) or benzolsulfonyl group.
  • Cbz Carbobenzyloxy
  • BOC tert-Butyloxycarbonyl
  • FMOC 9-Fluorenylmethyloxycarbonyl
  • Alkanoyl group such as the Ace
  • Yin compounds of formula I also denotes N-Q, wherein Q is a group selected from
  • Z 1 is S, O, NR 3 ;
  • Z 2 , Z 2 ′, Z 3 independently denote CR 5 , CR 6 or N;
  • R 5 , R 5 ′, R 6 , R 7 independently denote H, Hal, NR 3 R 4 , NO 2 , straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , NR 3 CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , NO 2 , OR 3 , Het, Ar, Cyc, or denote Ar, Het or Cyc;
  • R 8 denotes H, methyl or straight chain or branched alkyl having 2 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , NR 3 CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 or NO 2 ;
  • R 3 , R 4 denote each independently H or a straight chain or branched alkyl group having 1 to 12 carbon atoms;
  • Hal denotes F, Cl, Br or I
  • Het denotes a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fused-bicyclic and having 3- to 8-members and containing 1 to 4 heteroatoms selected from N, O and S, which may be substituted by 1 to 3 substituents selected from R 5 , Hal and OR 3 ;
  • Ar denotes a 6-membered carbocyclic aromatic ring or a fused or non fused bicylic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R 5 , OR 3 and Hal;
  • Cyc denotes a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R 5 or Hal or OH.
  • Q is selected from the group
  • R 5 , R 5 ′, R 7 and R 8 have the meaning given above.
  • the invention relates to acid addition salts of compounds of formula I or Ia, wherein R 5 , R 5 ′, R 6 , R 7 are independently H, Hal, NR 3 R 4 , NH 2 , N(CH 3 ) 2 , phenyl, 2-,3- or 4-hydroxy or methoxyphenyl, alkyl, CF 3 , alkoxy (Oalkyl), hydroxyalkylen, alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, NHalkyl, CO—N-morpholinyl, CON(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , CO-1-piperidinyl, CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl, CH 2 —N-morpholinyl, CH 2 N(H)COCH 3 ,
  • Q is selected from the group:
  • the method of the present invention can e.g. be used for the preparation of the following compounds from their corresponding racemates or by synthesis using intermediates that are obtained in enantiomerically enriched or pure form according to the process of the present invention:
  • unsubstituted means that the corresponding radical, group or moiety has no substituents.
  • substituted means that the corresponding radical, group or moiety has one or more substituents.
  • a radical has a plurality of substituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical. Even though a radical has a plurality of a specific-designated substituent the expression of such substituent may differ from each other (e.g. methyl and ethyl). It shall be understood accordingly that a multiple substitution by any radical of the invention may involve identical or different radicals. Hence, if individual radicals occur several times within a compound, the radicals adopt the meanings indicated, independently of one another.
  • alkyl or “alkyl group” refers to acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e. C 1 -C 10 -alkanyls.
  • alkyl radicals are methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,
  • n-pentyl iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl,
  • n-hexadecyl n-octadecyl, n-icosanyl, n-docosanyl.
  • alkyl denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced independently from one another by Hal.
  • a preferred embodiment of alkyl denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4 atoms may be replaced independently from one another by Hal.
  • alkyl denotes unbranched or branched alkyl having 1-4 C atoms, in which 1-3 H atoms can be replaced independently from one another by Hal, particularly by F and/or Cl. It is most preferred that alkyl denotes unbranched or branched alkyl having 1-6 C atoms.
  • C 1-4 -alkyl is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especially methyl, ethyl, propyl or trifluoromethyl. It shall be understood that the respective denotation of alkyl is independently of one another in any radical of the invention.
  • cycloalkyl or “Cyc” for the purposes of this invention refers to saturated and partially unsaturated non-aromatic cyclic hydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3 to 12, more preferably 3 to 9 carbon atoms.
  • the cycloalkyl radical may also be part of a bi- or polycyclic system, where, for example, the cycloalkyl radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and desired ring member(s).
  • the bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cycloalkyl radical.
  • Suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl.
  • Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4 H atoms may be replaced independently of one another by Hal.
  • Preferred is C 3 -C 7 -cycloalkyl. More preferred is C 4 -C 7 -cycloalkyl. Most preferred is C 5 -C 7 -cycloalkyl, i.e. cyclopentyl, cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall be understood that the respective denotation of Cyc is independently of one another in any radical of the invention.
  • aryl or “carboaryl” for the purposes of this invention refers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14, preferably 3-12, more preferably 4 to 12, most preferably 5 to 10, highly preferably 6 to 8 carbon atoms, which can be optionally substituted.
  • aryl also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the aromatic cycle is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein via any desired and possible ring member of the aryl radical.
  • the bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical.
  • aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.
  • Preferred carboaryls of the invention are optionally substituted phenyl, naphthyl and biphenyl, more preferably optionally substituted monocylic carboaryl having 6-8 C atoms, most preferably optionally substituted phenyl.
  • Aryl is preferably selected from the following group: phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- or p-(N-methyl-
  • Het denotes preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazoM-, -4- or -5-yl, 1,2,4-triazo-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-
  • Het can thus also denote, preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-di-hydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or
  • Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl, 4-methylpiperazinyl, pyrrolidinyl, morpholinyl, dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,
  • halogen refers to one or, where appropriate, a plurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro) or iodine (I, iodo) atoms.
  • fluorine fluorine
  • bromine Br, bromo
  • chlorine Cl, chloro
  • iodine I, iodo
  • perhalogen refer respectively to two, three and four substituents, where each substituent can be selected independently from the group consisting of fluorine, chlorine, bromine and iodine.
  • Halogen preferably means a fluorine, chlorine or bromine atom.
  • Fluorine and chlorine are more preferred, particularly when the halogens are substituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF 3 and CF 3 O). It shall be understood that the respective denotation of Hal is independently of one another in any radical of the invention.
  • Formula I embraces the mixture of the respective enantiomers, preferably the racemic mixture of the respective enantiomers.
  • Enantiomers of compounds of formula I, and the S-enantiomers in particular, are useful drugs or building blocks for the synthesis of drugs, such as but not limited to glycosidase inhibitors.
  • the present invention provides conditions and solvent systems in combination with chiral acids that can be reliably employed in processes that provide efficient resolution of the racemate or other enantiomeric mixtures of formula
  • the invention relates to a process for preparing either enantiomer of a compound of formula I:
  • X denotes O or CH 2 ,
  • Y is NH or N-PG
  • PG denotes a protective group
  • n denotes 0 or 1
  • each of the respective entantiomers can be obtained by e.g. aqueous basic treatment and extraction from aqueous phase with suitable solvents.
  • the method of the invention is particularly useful to prepare compounds of foruma II, i.e the S-enantiomers of formula I:
  • the present invention relates to a process for the separation of the enantiomers of a compound of formula I, comprising the steps of:
  • step b) optionally heating the mixture obtained under step a) from about 30° C. to about 120° C., such as between 40° C. and 100° C. or between 45° C. and 80° C. or heating the mixture to the boiling point of the selected solvent and allowing the mixture to cool to room temperature;
  • n is preferably 0.
  • a very preferred racemate or other enantiomeric mixture of a compound of formula I is the compound of formula (I′) (1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine), and preferably its racemate:
  • the present application specifically relates to a process for preparing (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine of formula (Ib′)
  • Another preferred racemate or other enantiomeric mixture of a compound of formula I is the compound of formula (I′′) (1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine), and preferably its racemate:
  • the present application specifically relates to a process for preparing (S)-1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine of formula (Ib′′)
  • Very preferred chiral acids used for the chiral resolution of compound of formula (I) are selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid, (S)-phenylsuccinic acid, Dibenzoyl-D-tartaric acid, D-(+)-Di-tolylyltartaric acid, D-tartaric acid, Di-p-anisoyl-(D)-tartaric acid. These acids are preferably employed, if the S-enatiomer of the respective compound of formula I is desired, as the diastereomeric salts are crystallizing.
  • R-enantiomers of compounds of formula (I) can be either obtained from the respective R-enantiomers of the chiral acids mentioned above or from the liquor after crystallized S-enantiomer of compounds of formula I have been separated therefrom.
  • the chiral acids are used in a molar ratio to the compounds of formula I of between about 1 to 2 (i.e. about 0.5 equivalents based on the compounds of formula I) and about 3 to 1 (i.e. about 3 equivalents), more preferably in a molar ratio of about 1 to 1 (i.e. 1 equivalent) to about 2 to 1 (i.e. about 2 equivalents).
  • about 0.7, about 0.8 or about 0.9 equivalents are used for the selective crystallization according to the invention. Very preferred are about 0.8 equivalents.
  • Solvents and solvent mixtures that are preferably used for the process of the present invention, are H 2 O, MeCN (Acetonitrile), about 2 to about 50% H 2 O in EtOH (Ethanol), EtOH, 2 to 50% H 2 O in MeOH (Methanol), MeOH, 2 to 50% H 2 O in IPA (Isopropyl Alcohol), IPA, 2 to 50% MeOH in MEK (methyl ethyl ketone, 2-butanone), MEK, 2 to 50% MeOH in iPrOAc (isopropyl acetate), iPrOAc, dioxane. All percentages for solvent mixtures are given in volume percent, if not indicated otherwise.
  • An enantiomerically enriched mixture denotes a compound of Formula (Ib′), or (Ib′′) or related formula having an enantiomeric excess, as measured by methods well known by one skilled in the art, of 10% or more, preferably 50% or more, and more preferably more than 95%. Most preferably an enantiomerically enriched mixture denotes a compound of Formula (Ib′) or (Ib′′) or related formulae having an enantiomeric excess of more than 98%.
  • the present invention also relates to a process for manufacturing compound of formula (Ib′), (Ib′′) and to the compound as such.
  • the invention relates to the diastereomeric salts prepared according to the present invention.
  • Time for crysallisation ranges typically from about 0.5 hours to about 48 hours, such as from about 1 hour to about 24 hours, and at least about 2 hours.
  • Suitable bases for recovering the basic enantiomer from the respective diasteromeric salt used in the selective cystallisation process of the present invention include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate lithium hydroxide, and the like, preferably in aqueous solution. Preferably, from about 1.0 to about 4.0 molar equivalents of suitable base with respect to the compounds of formula I are used.
  • the resolution reactions are preferably heated above room temperature, before allowing to cool to room temperature or to lower temperatures.
  • the resolution reactions are preferably heated at the boiling point of the respective solvent or solvent mixture, preferably from about 40° C. to about 120° C.
  • the reaction temperature is about 50° C. to about 100° C. In one embodiment the temperature is raised to at least about 80° C.
  • % e.e means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
  • a chiral acid non-racemic acid is used for the resolution of the compounds of formula I.
  • these acids are enantiomerically pure or have at least an e.e. of 98% or 99%.
  • These acids include but are not limited to (1R or 1S)-10-camphorsulfonic acid, (1R or 1S)-3-bromocamphor-10-sulfonic acid, (D or L)-tartaric acid and substituted analogues such as (D or L)-diacetyltartaric acid, (D or L)-dibenzoyl tartaric acid, (D or L)-di-O,O′-p-toluoyl-tartaric acid, (D or L)-di-O,O′-o-toluoyl-tartaric acid, (R or S)-1,1′′-binaphthyl-2,2′′-diyl-hydrogenphosphate, (D or L)-N-acetyl-pheny
  • Preferred chiral acids are also the following: ( ⁇ )-Tartaric acid(+)-Camphor sulfonic acid, (2R,3R)-2′-chloro-tartranilic acid (2R,3R)-tartranilic acid, (2S,3S)-2′-methoxy-tartranilic acid, (R)-( ⁇ )-2-Chloromandelic acid, (R)-( ⁇ )-2-phenylpropionic acid, (R)-4-methyl-mandelic acid, (R)-alpha-methoxy-phenyl acetic acid, (R)-Anisyphos, (R)-BINAP phosphate, (R)-Chlocyphos, (R)-Phencyphos hydrate, (R)-phenylsuccinic acid, (S)-( ⁇ -methylbenzyl)phthalamic acid, (S)-′O-acetyl mandelic acid, (S)-4-bromo-mandelic acid, (
  • HOBt Hydrobenzotriazole
  • HPLC High Performance Liquid Chromatography
  • i-PrOH (2-propanol)
  • K 2 CO 3 potassium carbonate
  • LC Liquid Chromatography
  • MD Autoprep Mass directed Autoprep
  • MeOH methanol
  • MgSO 4 magnesium sulfate
  • MS mass spectrometry
  • MTBE Metal tert-butyl ether
  • the compounds according to Formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples. All reported yields are non optimized yields.
  • HPLC analyses were obtained using Agilent 1200 Series instruments as followed using % with UV detection (maxplot).
  • Mobile phase B Ethanol/Acetonitrile/Trifluoroacetic acid 50/50/0.2
  • the chiral HPLC methods described below may preferably be performed on an Agilent 1260 DAD instrument.
  • COLUMN Chiralcell OJ-H column (250 ⁇ 4.6) mm, 5 ⁇ m
  • COLUMN Chiralpak IA (250 ⁇ 4.6) mm, 5 ⁇ m
  • COLUMN Chiralcel OD-H (250 ⁇ 4.6) mm, 5 ⁇ m
  • COLUMN Chiralcell OJ-H column (250 ⁇ 20) mm, 5 ⁇ m
  • the SFC purifications were performed with a Prep SFC, THAR-SFC 80 and THAR-SFC 200.
  • COLUMN YMC Cellulose SB (250 ⁇ 30) mm, 5 ⁇ m; CO-SOLVENTS: 0.5%
  • Step 1 t-Butyl 4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate
  • the S-enantiomer of this compound can be obtained from the racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Step 2 Hydrochloride Salt of 1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine
  • Step 1 tert-butyl 4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate
  • Step 2 Hydrochloride Salt of 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine
  • the hydrochloride salt of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (20 g) was suspended in NaOH solution (1 M, 150 mL) and extracted with EtOAc (150 mL). The water layer was further extracted two times with EtOAc (50 mL). The combined organic layers were dried over MgSO 4 and filtered off. After evaporation of the solvent, the title compound was isolated as an oil (10 g). The aqueous layer was further basified to pH 12 (pH after the extraction was around 7-8) by addition of 2 M NaOH solution and further extracted with EtOAc. A second batch of the title compound (5 g) was isolated.
  • the title compound was prepared according to procedures reported in the literature and known by persons skill in the art, using 6-bromo-2,3-dihydro-1-benzofuran (1 g, 5.03 mmol) as starting material.
  • 6-bromo-2,3-dihydro-1-benzofuran (1 g, 5.03 mmol) in toluene (10 mL) was degassed for 30 min.
  • 1-ethoxy vinyl tributyltin (2.012 g, 5.53 mmol) and bis(triphenylphosphine)palladium dichloride (0.35 g, 0.50 mmol) were added at rt and stirred for 16 hours at 90° C.
  • the title compound was prepared according to procedures reported in the literature and known by persons skill in the art, using 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one (0.6 g, 3.7 mmol) as starting material.
  • 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one 0.6 g, 3.7 mmol
  • sodium borohydride 281 mg, 7.4 mmol
  • the completion of the reaction was monitored by TLC and the solvents were evaporated at 45° C. under vacuum.
  • Example 8 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine, hydrochloride Step 1: tert-butyl 4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate
  • the S-enantiomer of this compound can be obtained from the racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • the S-enantiomer of this compound can be obtained from the racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Step 1 tert-butyl 4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate
  • the S-enantiomer of this compound can be obtained from the racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • the S-enantiomer of this compound can be obtained from the racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Example 10 Resolution of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine with (S)-phenylsuccinic Acid: Preparation of (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (S)-phenylsuccicinic Acid
  • Example 10 The solid salt obtained in Example 10 is treated according to example 6, in order to obtain the free base (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (light yellow oil).
  • Example 12 Resolution of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine with (S)-4-chloromandelic Acid: Preparation of (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (S)-4-chloromandelic Acid
  • Example 12 The solid salt obtained in Example 12 is treated according to Example 6, in order to obtain the free base (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine.
  • Example 14 Resolution of 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine with D-Di-p-anisoyltartaric Acid: Preparation of (S)-1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine D-Di-p-anisoyltartaric Acid
  • Example 9 To a stirred solution of Example 9 (102 g, 439.7 mmol) in 5% water in MeOH (1236 mL, 12V), D-di-p-anisoyltartaric acid (92.86 g, 219.8 mmol) was added at rt. The mixture was refluxed for 30 min. All the material was initially dissolved. When the salt was formed it precipitated as a white solid. The mixture was stirred overnight at room temperature and the solid was collected by filtration and washed twice with 5% of water in methanol (2 ⁇ 1.0 L). The optical purities of the solid and filtrate were 87% ee and 68% ee respectively (Chiral HPLC Method B).
  • the solid was refluxed in methanol containing 5% of water 12 V (1.2 L) for 20 minutes. The suspension was allowed to cool to room temperature and stirred overnight before the solid was collected by filtration and washed twice with 5% of water in methanol (2 ⁇ 1.0 L). The optical purity of the solid was 94% ee (Chiral HPLC Method B). The solid was refluxed a second time in methanol containing 5% of water (1.2 L). The suspension was allowed to cool to room temperature and stirred overnight before the solid was collected by filtration and washed with 5% of water in methanol (1.2 L). The optical purity of the solid was 97.94% ee (Chiral HPLC Method B). The solid material was dried in vacuum to furnish the diastereomeric salt as white solid (65 g, 33% yield).
  • Example 14 was dissolved in water (100 mL) and the resulting solution was basified using 5N NaOH solution (200 mL). The compound was extracted with EtOAc (2 ⁇ 500 mL). The combined organic layer was washed with brine solution (500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to get the title compound. Yield: 89% (30.5 g, light yellow gum).
  • Step 1 tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate
  • Step 2 tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • the S-enantiomer of this compound can be obtained by use of the respective
  • Example 41 To a stirred solution of Example 41 (0.06 g, 0.7 mmol), diisopropylethylamine (0.4 mL, 0.32 mmol) in dry DCM (4.0 mL), acetic anhydride (0.96 mL, 1.05 mmol) was added at 0° C. and the resulting mixture was stirred for 5 h at rt. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated and the crude products were purified by flash chromatography to afford the title compound (colorless oil).
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Example 68 and Example 69 (R)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide and (S)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide
  • the S-enantiomer of this compound can also be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Example 65 and Example 66 (R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide and (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl-N-methylthiazole-5-carboxamide
  • Step 2 Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate
  • Example 5 To a stirred solution of Example 5 (1.5 g, 6.40 mmol) in dry DMF (15 mL), ethyl 2-bromothiazole-5-carboxylate (1.96 g, 8.32 mmol) and TEA (3.5 mL, 25.6 mmol) were added at rt and the reaction mixture was stirred at 120° C. for overnight. The reaction mixture was cooled to rt and was diluted with EtOAc. The organic layer was washed with brine (10 mL), water (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum. The crude product was purified by column chromatography to afford the title compound (off white solid).
  • Step 3 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic Acid
  • Step 4 (R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide and (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide
  • Example 65 (white solid).
  • the S-enantiomer of this compound can also be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Step 1 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine
  • Example 2 To a stirred solution of Example 2 (1 g, 4.2 mmol) in dry DMF (10 mL), Et 3 N (2.3 mL, 16.8 mmol) and 2-chloro-5-nitropyrimidine (0.74 g, 4.6 mmol) were added at rt and the resulting mixture was stirred at 120° C. for 20 h. It was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography to give the title compound (yellow solid).
  • Step 2 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Example 70 To a stirred solution of Example 70 (180 mg, 0.54 mmol) in dry pyridine (1.35 mL), acetic anhydride (0.06 mL, 0.65 mmol) was added at room temperature and the resulting mixture was stirred at 50° C. overnight. It was diluted with ethyl acetate (100 mL) and washed with HCl (1.5 N), water, brine and dried over Na 2 SO 4 . After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (yellow solid).
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Example 77 and Example 78 (R)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide and (S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide
  • Example 72 was submitted to chiral preparative HPLC (Method PD). The first eluting fraction was concentrated, affording Example 77 (pale yellow solid).
  • the S-enantiomer of this compound can also be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Step 3 Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate
  • Example 2 To a stirred solution of Example 2 (1.87 g, 6.94 mmol) in dry acetonitrile, potassium carbonate (2.87 g, 20.8 mmol, spectrochem) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate were added and the resulting mixture was at rt for 12 h. It was filtered through celite and concentrated. Dichloromethane (25 mL) was added and the solution was washed with water, brine and dried over Na 2 SO 4 . After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (white solid).
  • Step 4 Lithium 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate
  • Step 5 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide
  • the S-enantiomer of this compound can be obtained by use of the respective S-intermediate or from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.
  • Step 1 Ethyl (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate
  • Example 13 To a stirred solution of Example 13 (1.87 g, 6.94 mmol) in dry acetonitrile (10 mL), potassium carbonate (2.87 g, 20.8 mmol, Spectrochem) and ethyl 2-(methylsulfonyl) pyrimidine-5-carboxylate (1.6 g, 6.94 mmol, synthesis described in Example 98, steps, 1 and 2) were added. The resulting mixture was stirred at rt for 3 h. It was then filtered through celite and concentrated. The crude product was diluted with dichloromethane (25 mL), washed with water and dried over anhydrous Na 2 SO 4 .
  • Step 2 Lithium (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate
  • Step 3 (S) 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide
  • the S-enantiomer of this compound can also be obtained from its racemate by applying the processes and conditions described in examples 10, 11, 12, 13, 14 and 15.

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US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
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US11046712B2 (en) 2014-08-28 2021-06-29 Asceneuron Sa Glycosidase inhibitors
US12187741B2 (en) 2014-08-28 2025-01-07 Asceneuron Sa Glycosidase inhibitors
US11591327B2 (en) 2016-02-25 2023-02-28 Asceneuron Sa Acid addition salts of piperazine derivatives
US10995090B2 (en) 2016-02-25 2021-05-04 Asceneuron Sa Substituted dihydrobenzofuran glycosidase inhibitors
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US12157734B2 (en) 2016-02-25 2024-12-03 Asceneuron Sa Sulfoximine glycosidase inhibitors
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
US12398130B2 (en) 2016-02-25 2025-08-26 Asceneuron Sa Acid addition salts of piperazine derivatives
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
US12016852B2 (en) 2018-08-22 2024-06-25 Asceneuron Sa Pyrrolidine glycosidase inhibitors
US12195455B2 (en) 2018-08-22 2025-01-14 Asceneuron Sa Succinate and fumarate acid addition salts of piperazine derivatives

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